Elevated Levels of MMP12 Sourced from Macrophages Are Associated with Poor Prognosis in Urothelial Bladder Cancer

Overview

Journal BMC Cancer

Publisher Biomed Central

Specialty Oncology

Date 2023 Jun 30

PMID 37391708

Authors

Iliana K Kerzeli

Alexandros Kostakis

Polat Turker

Per-Uno Malmstrom

Tammer Hemdan

Artur Mezheyeuski

Douglas G Ward

Richard T Bryan

Ulrika Segersten

Martin Lord

Sara M Mangsbo

Affiliations

Soon will be listed here.

Abstract

Background: Urothelial bladder cancer is most frequently diagnosed at the non-muscle-invasive stage (NMIBC). However, recurrences and interventions for intermediate and high-risk NMIBC patients impact the quality of life. Biomarkers for patient stratification could help to avoid unnecessary interventions whilst indicating aggressive measures when required.

Methods: In this study, immuno-oncology focused, multiplexed proximity extension assays were utilised to analyse plasma (n = 90) and urine (n = 40) samples from 90 newly-diagnosed and treatment-naïve bladder cancer patients. Public single-cell RNA-sequencing and microarray data from patient tumour tissues and murine OH-BBN-induced urothelial carcinomas were also explored to further corroborate the proteomic findings.

Results: Plasma from muscle-invasive, urothelial bladder cancer patients displayed higher levels of MMP7 (p = 0.028) and CCL23 (p = 0.03) compared to NMIBC patients, whereas urine displayed higher levels of CD27 (p = 0.044) and CD40 (p = 0.04) in the NMIBC group by two-sided Wilcoxon rank-sum tests. Random forest survival and multivariable regression analyses identified increased MMP12 plasma levels as an independent marker (p < 0.001) associated with shorter overall survival (HR = 1.8, p < 0.001, 95% CI:1.3-2.5); this finding was validated in an independent patient OLINK cohort, but could not be established using a transcriptomic microarray dataset. Single-cell transcriptomics analyses indicated tumour-infiltrating macrophages as a putative source of MMP12.

Conclusions: The measurable levels of tumour-localised, immune-cell-derived MMP12 in blood suggest MMP12 as an important biomarker that could complement histopathology-based risk stratification. As MMP12 stems from infiltrating immune cells rather than the tumor cells themselves, analyses performed on tissue biopsy material risk a biased selection of biomarkers produced by the tumour, while ignoring the surrounding microenvironment.

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References

Takayama H, Nishimura K, Tsujimura A, Nakai Y, Nakayama M, Aozasa K . Increased infiltration of tumor associated macrophages is associated with poor prognosis of bladder carcinoma in situ after intravesical bacillus Calmette-Guerin instillation. J Urol. 2009; 181(4):1894-900. DOI: 10.1016/j.juro.2008.11.090. View

Marchioni M, Primiceri G, Ingrosso M, Filograna R, Castellan P, DE Francesco P . The Clinical Use of the Neutrophil to Lymphocyte Ratio (NLR) in Urothelial Cancer: A Systematic Review. Clin Genitourin Cancer. 2016; 14(6):473-484. DOI: 10.1016/j.clgc.2016.04.008. View

Hao Y, Hao S, Andersen-Nissen E, Mauck 3rd W, Zheng S, Butler A . Integrated analysis of multimodal single-cell data. Cell. 2021; 184(13):3573-3587.e29. PMC: 8238499. DOI: 10.1016/j.cell.2021.04.048. View

Lundberg M, Eriksson A, Tran B, Assarsson E, Fredriksson S . Homogeneous antibody-based proximity extension assays provide sensitive and specific detection of low-abundant proteins in human blood. Nucleic Acids Res. 2011; 39(15):e102. PMC: 3159481. DOI: 10.1093/nar/gkr424. View

Ng K, Qi X, Kong K, Cheung B, Lo C, Poon R . Overexpression of matrix metalloproteinase-12 (MMP-12) correlates with poor prognosis of hepatocellular carcinoma. Eur J Cancer. 2011; 47(15):2299-305. DOI: 10.1016/j.ejca.2011.05.032. View

Song D, Powles T, Shi L, Zhang L, Ingersoll M, Lu Y . Bladder cancer, a unique model to understand cancer immunity and develop immunotherapy approaches. J Pathol. 2019; 249(2):151-165. PMC: 6790662. DOI: 10.1002/path.5306. View

Rubin J, Lagas J, Broestl L, Sponagel J, Rockwell N, Rhee G . Sex differences in cancer mechanisms. Biol Sex Differ. 2020; 11(1):17. PMC: 7161126. DOI: 10.1186/s13293-020-00291-x. View

Szarvas T, Hoffmann M, Olah C, Szekely E, Kiss A, Hess J . MMP-7 Serum and Tissue Levels Are Associated with Poor Survival in Platinum-Treated Bladder Cancer Patients. Diagnostics (Basel). 2021; 11(1). PMC: 7824149. DOI: 10.3390/diagnostics11010048. View

Kerzeli I, Lord M, Doroszko M, Elgendy R, Chourlia A, Stepanek I . Single-cell RNAseq and longitudinal proteomic analysis of a novel semi-spontaneous urothelial cancer model reveals tumor cell heterogeneity and pretumoral urine protein alterations. PLoS One. 2021; 16(7):e0253178. PMC: 8262791. DOI: 10.1371/journal.pone.0253178. View

10.

Samstein R, Lee C, Shoushtari A, Hellmann M, Shen R, Janjigian Y . Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019; 51(2):202-206. PMC: 6365097. DOI: 10.1038/s41588-018-0312-8. View

11.

Xing S, Ferrari de Andrade L . NKG2D and MICA/B shedding: a 'tag game' between NK cells and malignant cells. Clin Transl Immunology. 2020; 9(12):e1230. PMC: 7754731. DOI: 10.1002/cti2.1230. View

12.

Chen Z, Zhou L, Liu L, Hou Y, Xiong M, Yang Y . Single-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma. Nat Commun. 2020; 11(1):5077. PMC: 7545162. DOI: 10.1038/s41467-020-18916-5. View

13.

McGowan P, Duffy M . Matrix metalloproteinase expression and outcome in patients with breast cancer: analysis of a published database. Ann Oncol. 2008; 19(9):1566-72. DOI: 10.1093/annonc/mdn180. View

14.

Lindskrog S, Prip F, Lamy P, Taber A, Groeneveld C, Birkenkamp-Demtroder K . An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer. Nat Commun. 2021; 12(1):2301. PMC: 8052448. DOI: 10.1038/s41467-021-22465-w. View

15.

Lima L, Oliveira D, Tavares A, Amaro T, Cruz R, Oliveira M . The predominance of M2-polarized macrophages in the stroma of low-hypoxic bladder tumors is associated with BCG immunotherapy failure. Urol Oncol. 2013; 32(4):449-57. DOI: 10.1016/j.urolonc.2013.10.012. View

16.

Lee G, Askari A, Malietzis G, Bernardo D, Clark S, Knight S . The role of CD40 expression in dendritic cells in cancer biology; a systematic review. Curr Cancer Drug Targets. 2014; 14(7):610-20. DOI: 10.2174/1568009614666140828103253. View

17.

Yang G, Shen W, Zhang Y, Liu M, Zhang L, Liu Q . Accumulation of myeloid-derived suppressor cells (MDSCs) induced by low levels of IL-6 correlates with poor prognosis in bladder cancer. Oncotarget. 2017; 8(24):38378-38388. PMC: 5503539. DOI: 10.18632/oncotarget.16386. View

18.

Jin F, Thaiparambil J, Donepudi S, Vantaku V, Piyarathna D, Maity S . Tobacco-Specific Carcinogens Induce Hypermethylation, DNA Adducts, and DNA Damage in Bladder Cancer. Cancer Prev Res (Phila). 2017; 10(10):588-597. PMC: 5626664. DOI: 10.1158/1940-6207.CAPR-17-0198. View

19.

Zeegers M, Bryan R, Langford C, Billingham L, Murray P, Deshmukh N . The West Midlands Bladder Cancer Prognosis Programme: rationale and design. BJU Int. 2009; 105(6):784-8. DOI: 10.1111/j.1464-410X.2009.08849.x. View

20.

Wallard M, Pennington C, Veerakumarasivam A, Burtt G, Mills I, Warren A . Comprehensive profiling and localisation of the matrix metalloproteinases in urothelial carcinoma. Br J Cancer. 2006; 94(4):569-77. PMC: 2361180. DOI: 10.1038/sj.bjc.6602931. View